The enediyne natural products are the most cytotoxic molecules in existence today, and their use as anticancer drugs has been demonstrated clinically. The natural enediynes have seen limited use as clinical drugs mainly because of substantial toxicity, however, various polymer-based delivery systems or antibody-drug conjugates (ADCs) have shown great clinical success or promise in anticancer therapy. Indeed, the poly(styrene-co-maleic acid)-conjugated neocarzinostatin (SMANCS®) has been marketed since 1994 for use against hepatoma. Various ADCs have been developed or are in varying stages of development, including a CD33 mAB-calicheamicin (CAL) conjugate (i.e., MYLOTARG®) for acute myeloid leukemia (AML), a CD22 mAB-CAL conjugate (inotuzumab ozogamicin) for non-Hodgkin lymphoma, as well as, several mAB-C-1027 conjugates for hepatoma and mAB-uncialamycin (UCM) conjugates for selected tumors. These examples clearly demonstrate that the enediynes can be developed into powerful drugs when their extremely potent cytotoxicity is harnessed and delivered to tumor cells.